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Inflammatory demyelinating diseases (IDDs), sometimes called Idiopathic (IIDDs) because the unknown etiology of some of them, and sometimes known as borderline forms of multiple sclerosis,[1] is a collection of multiple sclerosis variants, sometimes considered different diseases,[2][3] but considered by others to form a spectrum differing only in terms of chronicity, severity, and clinical course.[4][5]

Several previous MS variants have been recently separated from MS after the discovery of a specific auto-antibody. Those autoantibodies are currently anti-AQP4, anti-MOG and some anti-Neurofascins.[19]

The pathogenic mechanism is usually not related to the clinical course. Therefore, one given pathogenic underlying condition can yield several clinical diseases, and one disease can be produced by several pathogenic conditions.

The anti-mog spectrum in children is equally variated: Out of a sample of 41 children with MOG-antibodies 29 had clinical NMOSD (17 relapsing), 8 had ADEM (4 relapsing with ADEM-ON), 3 had a single clinical event CIS, and 1 had a relapsing tumefactive disorder. Longitudinal myelitis was evident on MRI in 76[percent]. It has also been noted that percentage of children with anti-mog antibodies respect a demyelinating sample is higher than for adults[37]

Some anti-neurofascin demyelinating diseases were previously considered a subtype of Multiple Sclerosis but now they are considered a separate entity, as it happened before to anti-MOG and anti-AQP4 cases. Around 10% of MS cases are now thought to be anti-Neurofascin disease in reality.[39]

Some cases of CIDP are reported to be produced by auto-antibodies against several neurofascin proteins. These proteins are present in the neurons and four of them have been reported to produce disease: NF186, NF180, NF166 and NF155.[40]

Antibodies against Neurofascins NF-155 can also appear in MS[41] and NF-186 could be involved in subtypes of MS[42] yielding an intersection between both conditions.

Several anti-TNF drugs like adalimumab[9][10] are commonly prescribed by a number of autoimmune conditions. Some of them have been reported to produce a CNS-demyelination compatible with, and by current knowledge indistinguishable from, standard MS.[11][12] Several other monoclonal antibodies like pembrolizumab,[13]nivolumab[14] and infliximab[15] have been also reported to produce MS artificially.

In most cases, the damage fulfills all pathological diagnostic criteria of MS and can therefore be classified as MS in its own right. The lesions were classified as pattern II in the Lassman/Lucchinetti system. Some lesions also showed Dawson fingers,[12] which is supposed to be a MS-only feature.

These recent problems with artificial anti-TNF-α autoimmunity also point to the possibility of tumor necrosis factor alpha involvement in some multiple sclerosis variants.

Also a previous subtype of MS associated to LHON has been described (LHON-MS)[8] It is a presentation of LHON with MS-like CNS damage.

It used to satisfy McDonalds definition for MS, but after demonstration that LHON can produce this kind of lesions, the "no better explanation" requirement does not hold anymore. It is not due to auto-antibodies, but to defective mitochondria instead.[44]

The symptoms of this higher form of the disease include loss of the brain's ability to control the movement of muscles, tremors, and cardiac arrhythmia.[45] and the lack of muscular control[46]

Apart of the previously cited spectrums (Anti-AQP4 diseases, Anti-MOG, Anti-NF and anti-TNF spectrums) there is a long list of MS variants, with possibly different pathogenesis, which are still idiopathic and considered inside the MS-spectrum.

Most atypical variants appear as tumefactive or pseudotumefactive variants (lesions whose size is more than 2 cm, with mass effect, oedema and/or ring enhancement)[47][48] Some cases of the following have shown anti-MOG auto-antibodies and therefore they represent MS cases only partially.

Schilder disease or diffuse myelinoclastic sclerosis: is a rare disease that presents clinically as a pseudotumoural demyelinating lesion; and is more common in children.[52][53]

Solitary sclerosis: This variant has been recently proposed (2012) by Mayo Clinic researchers.[54] though it was also reported by other groups more or less at the same time.[55][56] It is defined as isolated demyelinating lesions which produce a progressive myelopathy similar to primary progressive MS.

Myelocortical multiple sclerosis (MCMS), proposed variant with demyelination of spinal cord and cerebral cortex but not of cerebral white matter [57] Several atypical cases could belong here. See the early reports of MCMS<[58][59]

Opticospinal MS or Optic-spinal MS (OSMS): Old OSMS cases are now considered inside the NMO spectrum, but this does not apply to anti-AQP4 negative cases.[60] After the discovery of anti-AQP4 autoantibodies it was found that some cases of OSMS were AQP4-negative, and therefore, they are considered real MS cases. OSMS has its own specific immunological biomarkers[61] The whole picture is under construction and several reports exists about overlapping conditions.

Pure spinal multiple sclerosis: Patients with clinical and paraclinical features suggestive of cord involvement of multiple sclerosis (MS)-type albeit not rigidly fulfilling the McDonald criteria[62] Some inflammatory conditions are associated with the presence of scleroses in the CNS.[63]Optic neuritis (monophasic and recurrent) and Transverse myelitis (monophasic and recurrent)

LHON associated MS (LHON-MS), a presentation of LHON with MS-like CNS damage, and therefore a subtype of MS according to McDonalds definition.[8]

Oligoclonal negative MS: Some reports point to the possibility of a different pathogenesis[64] They represent around 5% of the cases[65] which is suspected to be immunogenetically different.[66] Their evolution is better than standard MS patients,[67]

Oligoclonal IgM positive MS, with immunoglobulin-M Bands (IgM-Bands), which accounts for a 30-40% of the MS population and has been identified as a predictor of MS severity.[68] It has been reported to have a poor response to interferon-beta but a better response to glatimer acetate instead[69]

OCB's types: OCBs are made up of activated B-cells. It seems that the molecular targets for the OCB's are patient-specific.[70]

Inside well defined MS (Lesions disseminated in time and space with no other explanation) there are atypical cases based in radiological or metabolic criteria. A four-groups classification has been proposed:[71]

Some reports state that those "types" were artificially made up trying to classify RRMS as a separate disease so that the number of patients was low enough to get the interferon approved by the FDA under the orphan drugs act.[74] Revisions in 2013 and 2017 removed the Progressive-Relapsing course and introduced CIS as a variety/course/status of MS, establishing the actual classification (CIS, RRMS, SPMS and PPMS). Nevertheless, these types are not enough to predict the responses to medications and several regulatory agencies use additional types in their recommendations lide Highly active MS, Malignant MS, Aggressive MS or Rapidly progressive MS.[75]

As of 2019, HAMS is defined as an RRMS phenotype with one or more of the following characteristics:[75]

DSS scale of 4 points at 5 years of onset of the disease

Multiple relapses (two or more) with incomplete recovery in the ongoing year

More than 2 brain magnetic resonance imaging (MRI) studies demonstrating new lesions or increase in the size of the lesions in T2, or lesions that enhance with gadolinium despite treatment (Clinical case 1 and 2).

No response to treatment with one or more DMTs for at least one year.

There is a group of patients who have defined clinical and radiological risk factors that predict a behavior of greater risk of conversion to HAMS, without having the diagnostic criteria of HAMS in a first clinical attack have predictors of high risk.

Occasionally, the term ‘malignant’ MS (MMS) has been used to describe aggressive phenotypes of MS, but this is another ambiguous term that—despite wide usage—means different things to different people.

In 1996, the US National MS Society (NMSS) Advisory Committee on Clinical Trials in Multiple Sclerosis, “malignant MS” was also included, namely, “disease with a rapid progressive course, leading to significant disability in multiple neurologic systems or death in a relatively short time after disease onset.”

Many authors reserve the term malignant for fulminant forms of MS that deteriorate so rapidly from the outset as to be almost monophasic, and result in death within months to a few years. One such example is the Marburg variant of MS, which is classically characterized by extensive necrotic and/or tumefactive lesions with mass effect.

Interestingly, despite recent (and increasing) emphasis on early detection of patients with aggressive MS, the original definition of MMS was not modified by the NMSS Advisory Committee in its latest publication in 2013 (Lublin et al., 2014).

Common to all definitions is the early, unexpected acquisition of disability followed by frequent relapses and highly active disease seen on MRI.

One definition can be based on EDSS score and the time to develop secondary progressive MS (SPMS) (Menon et al., 2013).

No consensus exists on the speed of progression or degree of disability sufficient for aggressive MS, but we can assume that reaching an EDSS score of 6 points probably represents an upper limit beyond which the risk-benefit ratio for an aggressive treatment is unfavourable.

Pragmatically, AMS has been defined as any type of MS that is associated with repeated severe attacks and accelerated accrual of disability—put more simply, ‘rapidly progressive’ MS (See below)

This kind of MS was previously reported to behave different that the standard progressive course,[76] being linked to Connexin 43 autoantibodies with pattern III lesions (distal oligodendrogliopathy)[77] and being responsive to plasma exchange[78]

In very rapidly progressive multiple sclerosis the use of immunosuppressive therapy (mitoxantrone/cyclophosphamide), rituximab, autologous haematopoietic stem cell therapy or combination therapy should be considered carefully.[79]

Some auto-antibodies have been found consistently across different MS cases but there is still no agreement on their relevance:

Anti-kir4.1: A KIR4.1 multiple sclerosis variant was reported in 2012[80] and later reported again,[81] which could be considered a different disease (as Devic's disease did before), and can represent up to a 47% of the MS cases

Anoctamin 2: Auto-antibodies against anoctamin-2 (ANO-2), one of the ion-channel proteins, have been reported consistently since 2013[82]

This finding is not universal. Most of the MS patients do not show auto-antibodies against ANO-2. Therefore, this points toward an ANO2 autoimmune sub-phenotype in MS.[83]

Later reports point towards a mimicry between ANO-2 and EBV-EBNA-1 protein[84]

Anti-Flotilin spectrum: The proteins Flotillin 1 and flotillin 2 have been recently identified as target antigens in some patients with multiple sclerosis. First 14 cases were reported together in the first report, and 3 new cases were reported later inside a cohort of 43 patients.[87]

Mutations in GJB1 coding for connexin 32, a gap junction protein expressed in Schwann cells and oligodendrocytes, that usually produce Charcot-Marie-Tooth disease. In some cases also MS (as defined by McDonalds criteria) can appear in these patients.[88]

Other auto-antibodies can be used to stablish a differential diagnosis from very different diseases like Sjögren syndrome which can be separated by Anti–Calponin-3 autoantibodies.[95]

The correlation between this genetic mutation and MS was challenged but in 2018 has been replicated by an independent team.[96] Notice that this results do not refer to general MS.

In general, NMO-like spectrum without known auto-antibodies is considered MS. Principal component analysis of these cases show 3 different kinds of antibody-negative patients. The metabolite discriminators of RRMS and Ab-NMOSD suggest that these groupings have some pathogenic meaning.[97]

This is a specially aggressive clinical course of progressive MS[104] that has been found to be caused by a special genetic variant. It is due to a mutation inside the gene NR1H3, an arginine to glutamine mutation in the position p.Arg415Gln, in an area that codifies the protein LXRA.[105]

Some researchers propose to separate primary progressive MS from other clinical courses. PPMS, after recent findings seem to point that it is pathologically a very different disease.[106][107][108][109]

Some authors think since long ago that primary progressive MS should be considered a disease different from standard MS,[110][111] and it was also proposed that PPMS could be heterogeneous[112]

Clinical variants have been described. For example, Late Onset MS.[113] Since 2016, a special clinical variant of "rapidly progressive" MS has been found to be different from RRMS and other kinds of PPMS.[104] It is due to a mutation inside the gene NR1H3, an arginine to glutamine mutation in the position p.Arg415Gln, in an area that codifies the protein LXRA.

For the rest of the progressive cases, it has been found that the lesions are diffuse instead of the normal focal ones,[114] and are different under MR spectroscopy.[115] RRMS and PPMS patients also show differences on the retinal layers yields examined under OCT.[116]

Some authors have proposed a dual classification of PPMS, according to the shape of edges of the scars, in MS-like and ADEM-like[117]Proteomic analysis have shown that two proteins, Secretogranin II and Protein 7B2, in CSF can be used to separate RRMS from PPMS[118]

Recently, the hypothesis of PPMS being apart from RRMS/SPMS is taken further credibility due that it was shown that CSF from PPMS patients can carry the disease to other animals, producing neurodegeneration in mice[106] and that Normal Appearing White Matter (NAWM) structure is also different[119]

The predominant lesions in PPMS are slowly expanding lesions with T cells, microglial, and macrophage-associated demyelination in close similar to pattern I demyelination[120]

As of 2019 it has been found that the profile of T-cells is different in PPMS and SPMS[121]

MS can be considered among the acquired demyelinating syndromes with a multiphasic instead of monophasic behaviour.[122] Multiple sclerosis has a prodromal stage in which an unknown underlying condition, able to damage the brain, is present, but no lesion has still developed.

MS is usually classified in clinical types, though they are unrelated to the underlying pathology. Some critical reports say that the current "types" were artificially made up, just to treat RRMS as a separate disease. In this way the number of patients was low enough to enter the orphan drugs act, and get the interferon approved by the FDA under this schema.[123] Recent reviews state that all types are a mixture of inflammation and neurodegeneration, and that all types should be considered the same disease.[124]

The first manifestation of MS is the so-called Clinically isolated syndrome, or CIS, which is the first isolated attack. The current diagnosis criteria for MS do not allow doctors to give an MS diagnosis until a second attack takes place. Therefore, the concept of "clinical MS", for an MS that can be diagnosed, has been developed. Until MS diagnosis has been established, nobody can tell whether the disease one is dealing with is MS.

Cases of MS before the CIS are sometimes found during other neurological inspections and are referred to as subclinical MS.[125]Preclinical MS refers to cases after the CIS but before the confirming second attack.[126] After the second confirming attack the situation is referred to as CDMS (clinically defined multiple sclerosis).[127]

CIS itself is sometimes considered itself as a disease entity, different from MS. Even if they share the same underlying condition CIS is not MS given that it lacks the presence of lesions.[128] Approximately 84% of the subjects with CIS experience a second clinical demyelinating event and are diagnosed with clinically definite MS (CDMS) within 20 years.

Silent MS has been found in autopsies before the existence of MRI[129] showing that the so-called "clinical definitions" cannot be applied to around 25% of the MS cases.[130] Currently a distinction is made between "silent" and subclinical.

In absence of attacks, sometimes a radiological finding suggestive of demyelination (T2 hyperintensities[131]) can be used to establish a pre-diagnosis of MS. This is often named "Radiologically Isolated Syndrome" (RIS). Cases before the first attack or CIS are subclinical in the sense that they do not produce clinical situations.

If a second radiological event appears without clinical consequences, the clinical situation is named "Silent MS" (Okuda criteria).[132] Anyway, it is reported that all MS cases have an active subclinical phase before the CIS[133]

It has been noted that some aspects of the MS underlying condition are present in otherwise healthy MS patients' relatives,[134] suggesting a wider scope for the "silent MS" term.

In these cases Interleukin-8 is a risk for clinical conversion.[135] It has also been proposed that always exists a subclinical phase in the beginning of every MS case, during which the permeability of the BBB can be used for diagnosis[136]

It is also under investigation whether MS has a prodrome, i.e., a preliminary stage in which the disease exists with non-specific symptoms. Some reports point to a prodrome of several years for RRMS and decades for PPMS.[137]

Relapsing-Remitting MS is considered aggressive when the frequency of exacerbations is not less than 3 during 2 years. Special treatment is often considered for this subtype.[138] According to these definition aggressive MS would be a subtype of RRMS. (See above)

Other authors disagree and define aggressive MS by the accumulation of disability, considering it as a rapidly disabling disease course[139] and therefore inside PPMS.

The aggressive course is associated to grey matter damage and meningeal inflammation, and presents a special intrathecal (meninges and CSF) inflammatory profile.[140]

MS cases are rare before puberty, but they can happen. Whether they constitute a separate disease is still an open subject. Anyway, even this pubertal MS could be more than one disease, because early-onset and late-onset have different demyelination patterns[143]

Pediatric MS patients tend to have active inflammatory disease course with a tendency to have brainstem / cerebellar presentations at onset. Due to efficient repair mechanisms at early life, pediatric MS patients tend to have longer time to reach EDSS 6 but reach it at earlier age.[144]

Given that the etiology of MS is unknown, the current definitions of MS are all based on its appearance. The most commonly used definition, the McDonald criteria, requires just the presence of demyelinating lesions separated in space and time, together with the exclusion of every known demyelinating condition.

This unspecific definition has been criticized. For some people this has turned MS into a heterogeneous condition with several underlying problems.[146] Besides, the complementary problem also exists. Given that McDonalds-MS is based just in the distribution of the lesions, even twins with the same underlying condition can be classified different[147]

Finally, the "exclusion of every other known disease" condition also creates problems. Rightfully classified MS patients can be rightfully classified out of the spectrum when their particular underlying problem is discovered. For example, neuromyelitis optica was previously considered MS and currently is not, even if it appears that the MS definition has not changed.

McDonald criteria propose a clinical diagnosis based on a pathological definition, saying that the focus for diagnosis "remains on the objective demonstration of dissemination of lesions in both time and space" (DIT and DIS). But given that other diseases produce similar lesions, it is also required that those lesions cannot be explained by any other known disease.

This open definition present problems.[150] For example, before the discovery of anti-AQP4 in 2006, most optic-spinal MS patients were classified rightfully as MS. Currently they are classified as NMO. Both diagnosis are correct even though the definition has not (apparently) changed.

According to some pathologists, a pathological definition is required because clinical definitions have problems with differential diagnosis[151] and they always use a pathological definition on articles about post-mortem retrospective diagnosis, but for practitioners that need a diagnosis as soon as possible MS is often regarded as a pure clinical entity, defined simply by a positive result in the standard clinical case definition being then named "clinically definite MS" (CDMS, Poser) or simply "MS" (McDonald).[152]

Both definitions lead to different results. For example, confluent subpialcortical lesions are the most specific finding for MS, being exclusively present in MS patients.[153] but can only be detected post-mortem by an autopsy[154] Therefore, any other diagnosis method will have false positives.

There is no known etiology for MS and therefore no etiology-based definition is possible. Comparison to a post-mortem retrospective diagnosis is possible, but useless to practitioners and short-term researchers, and it is not usually done. Therefore, all meanings for the words "Multiple Sclerosis" are somehow diffuse.

The pathological definition based on proven dissemination in time and space has problems. For example, it leaves situations like RIS (radiologically isolated syndrome) outside the MS spectrum because the lack of proof, even in the case that this condition later could shown the same pathogenic conditions than MS cases.[155]

Besides, usually the term "multiple sclerosis" is used to refer to the presence of the unknown underlying condition that produces the MS lesions instead to the mere presence of the lesions. The term MS is also used to refers to the process of developing the lesions.[156]

Some authors instead speak about the biological disease vs. its clinical presentation.[157]

Anyway, the precise meaning in each case can be normally deduced from the context.

Given that several definitions of MS coexist, some authors are referring to them using whether CDMS for Poser positives, or McDonalds-MS with a prefix for McDonalds positives, including the release year in the prefix.[158]

The 2010 revision of the McDonald criteria[159] allows the diagnosis of MS with only one proved lesion (CIS). Consistently, the later revision for the MS phenotypes in 2013 was forced to consider CIS as one of the MS phenotypes.[160]

Therefore, the former concept of "Conversion from CIS to MS", that was declared when a patient had a second MS attack, does not apply anymore. More accurate is now to speak about conversions from the CIS phenotype to other MS phenotype.[161]